Cyanuric chloride catalyzed Beckmann rearrangement of ketoximes in biodegradable ionic liquids

Article abstract of DOI:10.1016/j.tet.2011.12.051

Imidazolium-based ionic liquids (ILs) containing ester moieties in the side chain were successfully used as an alternative to traditional ILs in the Beckmann rearrangement of ketoximes catalyzed by 2,4,6-trichloro[1,3,5]triazine. The procedure is mild and suitable for both aromatic and cycloaliphatic substrates affording the rearrangement products in good to quantitative yields. The process is eco-sustainable since these ILs are biodegradable and in addition they can be recovered and reused.

Full text of DOI:10.1016/j.tet.2011.12.051

Tetrahedron 68 (2012) 1947e1950
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyanuric chloride catalyzed Beckmann rearrangement of ketoximes
in biodegradable ionic liquids
,
b
b
Angelamaria Maia a , Domenico C.M. Albanese , Dario Landini
*
a Istituto CNR-ISTM, via Golgi 19, 20133 Milano, Italy
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, via Venezian 21, 20133 Milano, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2011
Received in revised form 6 December 2011
Accepted 19 December 2011
Available online 23 December 2011
Imidazolium-based ionic liquids (ILs) containing ester moieties in the side chain were successfully used
as an alternative to traditional ILs in the Beckmann rearrangement of ketoximes catalyzed by 2,4,6-
trichloro[1,3,5]triazine. The procedure is mild and suitable for both aromatic and cycloaliphatic sub-
strates affording the rearrangement products in good to quantitative yields. The process is eco-sus-
tainable since these ILs are biodegradable and in addition they can be recovered and reused.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Biodegradable ionic liquids
Organocatalysis
Beckmann rearrangement
Cyanuric chloride
Amides
1. Introduction
Biodegradable ILs were prepared by Boethling et al. starting
from the same principles used to improve biodegradation of the
The Beckmann rearrangement is an important reaction for the
transformation of ketoximes into amides, which has been suc-
structurally closed surfactants.9 Gathergood and Scammells were
the first to introduce functional groups, which would be susceptible
to enzymatic hydrolysis (esters/amides) into the IL imidazolium
cation side chain. They found that incorporation of an ester group
into the IL side chain significantly improved the biodegradation,
whereas amide analogues proved resistant to biodegradation. The
presence of the ester in the side chain, in fact, reasonably provides
a site for possible enzymatic cleavage to give the parent imidazo-
lium fragment and the corresponding primary alcohol that can
cessfully utilized to produce -caprolactam and lauryl lactam in
3
industry.1 It generally requires high reaction temperatures and an
excess or stoichiometric quantities of strongly acidic and dehy-
drating media.1 As a consequence, this reaction leads to large
amounts of by-products and is not applicable to sensitive sub-
strates. Among the various attempts of realizing a clean Beckmann
rearrangement under milder conditions,2 the use of room tem-
perature ionic liquids (ILs) has recently been reported.3e6
Ionic liquids (ILs) are attracting increasing interest as a potential
eco-sustainable alternative to harmful volatile organic solvents
(VOCs) that should be utilized only in limited quantities due to their
significant environmental impact.7 They possess many appealing
properties that include extremely low volatility, low flammability,
ease of recovery and recycling, and applicability to catalytic pro-
cesses.7 However, their excellent thermal and chemical stability,
often combined with water solubility, could raise concerns about
the potential for IL accumulation in the environment. As a conse-
quence, additional factors, such as biodegradability and toxicity,
need to be carefully investigated before processes are scaled-up in
ionic liquids.7g,8
readily be metabolized via fatty acid b
-oxidation.10e12
It is worth noting, however, that favourable biodegradability
must be balanced by the required stability of the solvent and
practical applicability. In catalytic hydrogenation reactions, for ex-
ample, imidazolium ILs are preferred to the more biodegradable
pyridinium salts due to their higher stability. In a recent paper,
Gathergood et al. reported that trans-cinnamaldehyde is selectively
hydrogenated to hydrocinnamaldehyde with little or no over-
reduction of the aldehydic group in biodegradable imidazolium-
based ILs containing ester and ether moieties in the side chain.13
The selectivities are in all cases higher than those found in com-
mon organic solvents and in conventional ILs. Analogous
pyridinium-based ILs were synthesised by Scammells et al. and
utilized as the solvent in DielseAlder reactions of cyclopentadiene
with a range of dienophiles.14 The results showed that both yield
and endo-selectivity were clearly enhanced in these biodegradable
* Corresponding author. Tel.: þ39 0 250314162; fax: þ39 0 250314159; e-mail
address: angelamaria.maia@istm.cnr.it (A. Maia).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.051

1948
A. Maia et al. / Tetrahedron 68 (2012) 1947e1950
Br–
ILs when compared with those performed in molecular organic
solvents.14
Br
On-Bu
NMI
N
Recently, our group successfully utilized 1-hexyl-3-
methylimidazolium-based ILs as an alternative to common VOCs
in the Beckmann rearrangement of a representative series of
ketoximes promoted by catalytic amounts of 2,4,6-trichloro[1,3,5]
triazine (cyanuric chloride, TCT).15 The reactions were found to be
fully regioselective, affording the N-substituted amides in very
good to quantitative yields.15 In view of the scale-up of this fun-
damental reaction we envisaged the possibility of using more
eco-sustainable solvents, such as biodegradable and/or low
toxicity ILs. However, since the reaction medium must be strongly
acidic, it was very important to verify the applicability of bio-
degradable ILs containing ester moieties in the side chain under
these conditions.
+
O
N
O
O
On-Bu
Me
3a
NMI = N-Methylimidazole
MY
acetone
24 h, r.t.
Y–
On-Bu
N
+
N
Me
3b-d
3b Y = ClO4
3c Y = BF4
3d Y = PF6
Scheme 2. Synthesis of ionic liquids 3bed.
Here we wish to report on the TCT-catalyzed Beckmann rear-
rangement of a range of representative aromatic and cycloaliphatic
ketoximes 1aeg to the corresponding amides 2aeg in biodegrad-
able 3-methyl-1-(n-butoxycarbonylmethyl) imidazolium-based
ionic liquids [BuOCOCH2mim][Y] 3bed (Scheme 1). The results
have been compared with those obtained in the common 1-hexyl-
3-methylimidazolium-based ILs (30bed) under the same reaction
conditions.
extraction with MTBE or by direct chromatography (silica gel) of
the reaction mixture (eluant ethyl acetate/petroleum ether) and
identified (1H NMR spectroscopy) by comparison with the au-
thentic sample.15
As reported in Table 1, the ketoximes 1aeg selectively rear-
ranged affording the N-substituted amides 2aeg generally in ex-
cellent yields (85e97%). In the case of non-symmetrical ketoximes
1bee, only one of the two possible amides was isolated. In line with
the Beckmann mechanism, the reaction times change with the
nature of the ketoxime: with electron-withdrawing substituents on
the aromatic ring (Cl, Table 1, entry 4) the rearrangement is slower
than that of the unsubstituted oxime 1b (2.7 h for 1d instead of 0.75
for 1b). By contrast, the reactions are faster with electron-donating
substituents like OH and OCH3 (0.42 and 0.33 for 1c and 1e,
respectively).
OH
N
O
TCTcat, 60 °C
R1
R2
R2
NHR1
3b-d
1a-g
2a-g
–
[BuOCOCH2mim][Y] 3b-d
3b, Y = ClO4
–
3c, Y = BF4
–
Interestingly, a high yield (85%) of lauryl lactam (2f), the nylon
12 monomer, was obtained from the cyclododecanone oxime (1f) in
the presence of 20 mol % of catalyst (TCT) after 2 h (Table 1, entry 6).
However, unlike 1f, the reaction of the six-membered cyclohexa-
3d, Y = PF6
1,2a R1 = R2 = Ph
1,2b R1 = Ph, R2 = Me
1,2c R1 = 4-C6H4-OH, R2 = Me
1,2d R1 = 4-C6H4-Cl, R2 = Me
1,2e R1 = 2-C6H4-OMe, R2 = Me
1,2f R1– R2 = (CH2)11
none oxime (1g) gave the product -caprolactam (2g) in poor yield
3
(30%) under the same conditions (Table 1, entry 7). Analogous be-
haviour was obtained by Ishihara and Yamamoto in CH3CN with
cyanuric chloride17 and more recently by Deng et al. with an or-
ganophosphorus catalyst.18
1,2g R1– R2 = (CH2)5
Comparison with the corresponding 1-hexyl-3-methylimida-
zolium-based ILs [hmim][Y] [Y¼ClO4 (30b), BF4 (30c), PF6 (30d)]
shows that both yields and reaction times are similar in all cases
(Table 2). The higher reactivity in ILs if compared with that found in
acetonitrile (Table 1, entry 1) is likely due to the involvement of the
hydrogens of the imidazolium cation (in particular the most acidic
H-2) in the rearrangement reaction.15,17 In this case no Lewis acids
or Brǿnsted acids were necessary as cocatalysts.15,17 In addition, in
ILs, due to their ionic nature, both the cation and the anion are
engaged in the reaction so producing a different reactivity of the
charged species depending on the IL-solute interactions.7 This can
explain the different reaction times found for the ILs 3bed
(Table 2).
Finally, almost quantitative recycling of the IL 3bed was ach-
ieved without significant loss of activity. Thus, the residue obtained
by continuous extraction of the reaction product can be reused after
removal of trace amounts of MTBE and dehydration under high
vacuum.19
For example, the benzophenone oxime (1a) rearranged to the
corresponding amide 2a in similar reaction times and yield of the
first run for almost two cycles in [BuOCOCH2mim][ClO4] 3b (Table
2, entries 2,3) and in [BuOCOCH2mim][PF6] 3d (Table 2, entries
10,11).
Scheme 1. Beckmann rearrangement of ketoximes 1aeg.
2. Results and discussion
The synthesis of the ILs 3bed was carried out in two steps to
give 3-methyl-1-(n-butoxycarbonylmethyl)imidazolium bromide
(3a) followed by halide anion exchange, to ClO4, BF4, PF6, according
to a previously reported method (Scheme 2).11,16
In the TCT-catalyzed rearrangement process, the oximes 1aeg
(0.6 mmol) were dissolved in the ILs (3bed) (2 mL) and combined
with the appropriate quantity of catalyst (TCT w 6e20 mol %).
Catalyst amounts of w6 mol % for 1aee and 20 mol % for 1f and 1g
were found to be a good compromise for obtaining satisfactory
reaction times and yield. With a lower TCT quantity (2 mol %) the
time remarkably increased reducing the conversion to the amide.
On the other hand, the higher quantity of catalyst (20%), required
for 1f and 1g (Table 1, entries 6 and 7), is due to the well known
lower tendency to rearrange of these aliphatic oximes.1,17 The
mixture was left under stirring at 60 ꢀC and monitored by TLC
until completion. The amide was isolated by continuous

A. Maia et al. / Tetrahedron 68 (2012) 1947e1950
1949
Table 1
TCT-catalyzed Beckmann rearrangement of oximes 1aeg in [BuOCOCH2mim][BF4], at 60 ꢀCa
Entry
Ketoxime
Amide
Cat (mol %)
5.6
Time (h)
Yieldb (%)
O
OH
N
1
0.68 (1.02)c
94
95
Ph
NHPh
Ph
Ph
1a
N
2a
OH
Me
O
2
3
5.6
5.6
0.75
0.42
Me
O
NHPh
2b
Ph
1b
OH
Me
OH
N
90
97
86
Me
N
H
HO
2c
1c
OH
Me
Cl
N
O
4
5.6
2.7
Me
N
H
Cl
2d
1d
OH
Me
N
O
Me
N
H
5
5.6
0.33
OMe
OMe
2e
1e
O
N
NH
OH
6
20
2.0
85
1f
2f
O
N
NH
OH
7
20
2.0
30
1g
2g
a
A solution of oxime (0.6 mmol) and TCT (5.6e20 mol %) in the IL (2 mL).
Isolated yield by chromatography of the IL solution.
Time for the same reaction performed in CH3CN is reported under brackets.
b
c
3. Conclusion
The process is eco-sustainable since these ILs can be easily re-
covered and reused several times and in addition they are
biodegradable.
The results as a whole show that ILs 3bed, that contain ester
moieties in the side chain, can be successfully utilized even in
catalytic Beckmann-type reactions that are known to require
strongly acidic media. Under these conditions this novel class of ILs
represent a valid alternative to traditional imidazolium-based ILs
30bed. The procedure is mild and suitable not only for aromatic
but also for cycloaliphatic ketoximes, such as cyclododecanone
oxime (1f), affording the rearrangement products in good to
quantitative yield.
4. Experimental section
4.1. General remarks
€
Melting points were determined on a BUCHI 535 and are
corrected. NMR spectra were recorded on Bruker AC 300 or AC
200 spectrometers, operating at 300.13 or 200.13 MHz for 1H

1950
A. Maia et al. / Tetrahedron 68 (2012) 1947e1950
Table 2
Spectroscopic properties of 3c and 3d are identical to those pre-
viously reported.16
Effect of the IL nature and catalyst amount on the Beckmann rearrangement of
benzophenone oxime 1a, at 60 ꢀCa
Entry
Ionic liquid
Cat (mol %)
Time (h)
Yield (%)
4.3. Typical procedure for the TCT-catalyzed Beckmann
rearrangement
1
2
3
4
5
6
7
8
[BuOCOCH2mim][ClO4] 3b
5.8
5.8
5.8
10
10
5.8
10
0.42
0.58
0.58
0.33
0.50
0.68
0.50
0.50
0.58
0.58
0.58
0.50
0.40
93
95
92
92
95
94
85
92
85
90
96
95
90
3bb
3bc
In a dry flask, ketoxime 1a (118 mg, 0.6 mmol) was dissolved in
the ionic liquid 3b (2 mL, 2.34 g) and 2,4,6-trichlorotriazine was
added (6.2 mg, 0.034 mmol). After stirring for 40 min at 60 ꢀC the
reaction mixture was directly extracted with MTBE by a liquid-
eliquid continuous extraction apparatus. The resulting MTBE so-
lution of 2a was filtered over a silica plug (eluant AcOEt/PE 1:4) to
remove trace amounts of 3b. Evaporation of the solvent under re-
duced pressure afforded 106 mg of N-phenyl-benzamide (2a)
(106 mg, 90%), as a white solid, mp 164 ꢀC (lit.20 164e165 ꢀC). After
removal of trace amounts of MTBE, followed by drying under vac-
uum, the IL residue 3b (2.20 g, yield 95%) could be reused for fur-
ther reactions.
3b
[hmim][ClO4] 30b
[BuOCOCH2mim][BF4] 3c
3c
[hmim][BF4] 30c
10
9
[BuOCOCH2mim][PF6] 3d
5.8
5.8
5.8
10
10
11
12
13
3db
3dc
3d
[hmim][PF6] 30d
10
a
A solution of oxime 1a (0.6 mmol) and TCT (5.8e10 mol %) in the IL (2 mL).
First recycle of ionic liquid.
Second recycle of ionic liquid.
b
c
Alternatively, the crude reaction mixture was directly subjected
to column chromatography on silica gel (eluant AcOEt/PE 1e7) to
give of N-phenyl-benzamide (2a) (111 mg, 94%). The ionic liquid 3c
was quantitatively recovered by eluting with AcOEt/MeOH (1:1).
The same procedure was used to generate amides 2beg, as pure
compounds, whose physical and spectroscopic data match those
previously reported.21
NMR and 75.3 or 50 MHz for 13C NMR. Coupling constants J are in
hertz. Chemical shifts were reported by using CHCl3 as external
standard (7.24 ppm for 1H NMR and 77.0 for 13C NMR). Column
chromatography on silica gel (230e400 mesh) was performed by
the flash technique. Petroleum ether (PE) refers to the fraction
boiling in the range of 40e60 ꢀC. ESI Mass spectra were measured
on a LCQ Advantage Thermo-Finnigan spectrometer. The water
content of each IL was measured using a coulometric Karl-Fischer
titrator (Metrohm 684 KF Coulometer). Samples were prepared by
dissolving 0.250e0.350 g of IL in anhydrous acetonitrile in a 2 mL
calibrated flask and duplicate determinations were performed on
each sample with results agreeing to within 5%. Potentiometric
titrations were carried out with a Metrohm 751 GPD Titrino using
a combined silver electrode isolated with a potassium nitrate
bridge.
Acknowledgements
The authors gratefully acknowledge the financial support pro-
ꢀ
vided by CNR (Rome, Italy) and Ministero dell’Istruzione, Universita
e Ricerca (MIUR).
References and notes
1. For reviews, see: (a) Gawly, R. E. Org. React. 1988, 35, 1e420 and references
therein; (b) Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.; John
Wiley and Sons: New York, NY, 2001; page 1415 and references therein.
2. Sardarian, A. R.; Shahsavari-Fard, Z.; Shahsavari, H. R.; Ebrahimi, Z. Tetrahedron
Lett. 2007, 48, 2639e2643.
4.2. Synthesis of ionic liquids
3. Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett. 2001, 42, 8441e8443.
4. Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 403e405.
5. Guo, S.; Du, Z.; Zhang, S.; Li, D.; Li, Z.; Deng, Y. Green Chem. 2006, 8, 296e300
and references therein.
4.2.1. Synthesis of [BuOCOCH2mim][ClO4] 3b. A dry flask was
charged with 3-methyl-1-(butoxy carbonylmethyl) imidazolium
bromide (3a) (16.81 g, 60 mmol) and acetone (50 mL) under
6. Yadav, L. D.; Srivastava, G. V. P. Tetrahedron Lett. 2010, 51, 739e743.
7. For general books and reviews on ionic liquids, see: (a) Ionic Liquids III A:
Fundamentals, Progress, Challenges and Opportunities-Properties and Structure;
Rogers, R. D., Seddon, K. R., Eds.; American Chemical Society: Washington DC,
2005; (b) Ionic Liquids III B: Fundamentals, Progress, Challenges and
Opportunities-Transformations and Processes; Rogers, R. D., Seddon, K. R., Eds.;
American Chemical Society: Washington DC, 2005; (c) Ionic Liquids in Synthesis,
2nd ed.; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH: Weinheim, 2008; (d)
Plechkova, N. V.; Seddon, K. R. Chem. Soc. Rev. 2008, 37, 123e150; (e) Kerton, F.
M. Alternative Solvents for Green Chemistry, RSC Green Chemistry Series; The
Royal Society of Chemistry: Cambridge, 2009; (f) Dupont, J.; de Souza, R. F.;
Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667e3692; (g) Maia, A. Mini-Rev. Org.
Chem. 2011, 8, 178e185.
8. Coleman, D.; Gathergood, N. Chem. Soc. Rev. 2010, 39, 600e637.
9. Boethling, R. S.; Sommer, E.; Di Fiore, D. Chem. Rev. 2007, 107, 2207e2227.
10. Gathergood, N.; Scammells, P. J. Aust. J. Chem. 2002, 55, 557e560.
11. Gathergood, N.; Garcia, M. T.; Scammells, P. J. Green Chem. 2004, 6, 166e175.
12. Garcia, M. T.; Gathergood, N.; Scammells, P. J. Green Chem. 2005, 7, 9e14.
13. Morrissey, S.; Beadham, I.; Gathergood, N. Green Chem. 2009, 11, 466e474.
14. Harjani, J. R.; Singer, R. D.; Garcia, M. T.; Scammells, P. J. Green Chem. 2009, 11,
83e90.
a
nitrogen atmosphere. After dissolution, NaClO4 (9.80 g,
80 mmol) was added and the suspension was stirred vigorously
for 24 h at room temperature. The complete exchange Brꢁ/ClO4ꢁ
was verified by argentometric titration. The white precipitate
was filtered off and washed with acetone (2ꢂ5 mL). The solvent
was removed by rotary evaporation and CH2Cl2 (50 mL) was
added. The organic solution was washed with saturated Na2SO4
aqueous solution (2ꢂ5 mL), dried with anhydrous Na2SO4 and
filtered. After removal of CH2Cl2 by rotary evaporation, the
viscous oil was dehydrated by heating at 60 ꢀC for 6 h under
high vacuum to give the title compound 3b (17.08 g, 95%). The
water content of 3b was determined to be 2321 ppm by Karl-
Fischer analysis; dH (300 MHz, CDCl3) 8.48 (s, 1H, ArH), 7.40 (s,
1H, ArH), 7.34 (s, 1H, ArH), 5.06 (s, 2H, NeCH2), 4.21 (t, 2H, J
6.6 Hz, OCH2), 3.96 (s, 3H, NeCH3), 1.67 (m, 2H, OCH2CH2), 1.38
15. Betti, C.; Landini, D.; Maia, A.; Pasi, M. Synlett 2008, 908e910 and references
therein.
(m, 2H, eCH2CH3), 0.93 (t, 3H,
J
7.4 Hz, CeCH3); dC
(75 MHz, CDCl3) 166 (C), 137.9 (CH), 123.8 (CH2), 123.0 (CH),
66.8 (CH2), 50.0 (CH2), 36.6 (CH3), 30.3 (CH2), 18.9 (CH2), 13.5
(CH3); m/z (ESI) 197.1 (100 BuOCOCH2mimþ), 493.2 (38
[BuOCOCH2mim]2ClOþ4 ).
16. Morrissey, S.; Pegot, B.; Coleman, D.; Garcia, M. T.; Ferguson, D.; Quilty, B.;
Gathergood, N. Green Chem. 2009, 11, 475e483.
17. Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 11240e11241.
18. Zhu, M.; Cha, C.; Deng, W.-P.; Shi, X.-X. Tetrahedron Lett. 2006, 47, 4861e4863.
19. Alternatively, the ILs 3bed, recovered by chromatography, were dissolved in
CH2Cl2, filtered on Celite, and reused after removal of the organic solvent under
vacuum.
20. Pi, H.-J.; Dong, J.-D.; An, N.; Du, W.; Deng, W.-P. Tetrahedron 2009, 65,
7790e7793.
21. De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272e6274.
4.2.2. Synthesis of [BuOCOCH2mim][BF4] 3c and [BuOCOCH2mim]
[PF6] 3d. Ionic liquids 3c and 3d are known compounds and have
been prepared by using the same procedure described above for 3b.